Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

The DIAMA study is evaluating new diagnostics that could provide a faster and more complete picture of drug resistance in TB.

Better detection of multidrug-resistant TB

Multidrug-resistant TB infections are becoming more common. A failure to identify drug resistance is bad for individual patients, and facilitates the wider spread of drug-resistant bacteria.

Culturing TB bacteria to assess resistance is technically difficult and can take up to four months. Molecular diagnostics are increasingly being used, but do not necessarily identify all resistance mutations.

The challenge

The DIAMA study is evaluating new options that could provide more rapid results on drug resistance than culturing. It builds on previous EDCTP funding and an infrastructure that undertakes continuous monitoring of TB patients for resistance to rifampicin.

Benin and Rwanda have established reference laboratories that can use the ‘Deeplex’ assay, which generates sequence information on genes conferring resistance to 14 key anti-TB drugs. In the first phase of the study, sputum samples will be shipped to the reference labs for Deeplex analysis and results compared with those obtained by the traditional culturing method.

In the second phase of the study, all participating countries will begin using two lower-tech tools – Molbio Diagnostics’ TrueNat test and the latest version of the Xpert molecular diagnostic platform – which do not require samples to be sent to a reference laboratory. Results will be compared with those obtained by Deeplex analysis. Newly developed software will be used to transmit results immediately to national TB programmes. Use of the new tools in patient management will be evaluated at two pilot sites. The project will also explore use of two faster alternatives to culture to monitor responses to treatment.

The project

Use of the new approaches could lead to more rapid identification of multidrug-resistant TB, and dramatically improve treatment in resource-poor settings, where treatment outcomes are typically much worse than in high-income countries.

Impact


crucial in

widening African

children’s access

to antiretrovirals

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Multidrug-resistant TB infections are becoming more common. A failure to identify drug resistance is bad for individual patients, and facilitates the wider spread of drug-resistant bacteria.

Culturing TB bacteria to assess resistance is technically difficult and can take up to four months. Molecular diagnostics are increasingly being used, but do not necessarily identify all resistance mutations.

The DIAMA study is evaluating new options that could provide more rapid results on drug resistance than culturing. It builds on previous EDCTP funding and an infrastructure that undertakes continuous monitoring of TB patients for resistance to rifampicin.

Benin and Rwanda have established reference laboratories that can use the ‘Deeplex’ assay, which generates sequence information on genes conferring resistance to 14 key anti-TB drugs. In the first phase of the study, sputum samples will be shipped to the reference labs for Deeplex analysis and results compared with those obtained by the traditional culturing method.

In the second phase of the study, all participating countries will begin using two lower-tech tools – Molbio Diagnostics’ TrueNat test and the latest version of the Xpert molecular diagnostic platform – which do not require samples to be sent to a reference laboratory. Results will be compared with those obtained by Deeplex analysis. Newly developed software will be used to transmit results immediately to national TB programmes. Use of the new tools in patient management will be evaluated at two pilot sites. The project will also explore use of two faster alternatives to culture to monitor responses to treatment.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Use of the new approaches could lead to more rapid identification of multidrug-resistant TB, and dramatically improve treatment in resource-poor settings, where treatment outcomes are typically much worse than in high-income countries.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M